Oral octreotide therapy and contraceptive methods

ABSTRACT

This invention relates to methods of administering oral octreotide therapy to a female subject relating to avoidance of combined oral contraceptives or use of a back-up method for contraception.

FIELD OF THE INVENTION

This invention relates to methods of administering oral octreotidetherapy to a female subject relating to avoidance of combined oralcontraceptives or use of a back-up method for contraception.

BACKGROUND

Although octreotide has been known as an injectable medicament for manyyears, it is only very recently that oral octreotide has been developed.Utilizing its proprietary formulation designated TPE® (transientpermeability enhancer), Chiasma, Inc developed a new formulation ofoctreotide acetate for oral delivery and entered the market under thebrand name MYCAPSSA® in June 2020. The TPE formulation facilitatesintestinal absorbance of drug molecules with limited intestinalbioavailability; the formulation protects the drug molecule frominactivation by the hostile gastrointestinal (GI) environment and at thesame time acts on the GI wall to induce a transient and reversibleopening of the paracellular route allowing permeation of the drugmolecules through the tight junctions. These two attributes ensure thatthe drug molecule reaches the bloodstream effectively in its activeform. TPE is a combination of excipients assembled in a process leadingto an oily suspension of hydrophilic particles containing medium-chainfatty acid salts and the active pharmaceutical ingredient (hereinoctreotide) suspended in a lipophilic medium.

It was contemplated that the formulation of octreotide acetate for oraldelivery might affect the bioavailability of other drugs administered topatients in need of oral octreotide therapy. Potential drug-druginteractions of the oral octreotide formulation with such drugs areherein evaluated.

SUMMARY

The inventors of the present invention have discovered that thebioavailability (absorption) of contraceptives (e.g., comprisinglevonorgestrel) is reduced when administered to a subject who isconcomitantly being administered oral octreotide. Levonorgestrel is acomponent of many combined oral contraceptives.

The inventors of the present invention have invented a method ofadministering oral octreotide to a female subject in need thereofwherein said subject is also in need of a contraceptive method,comprising

(a) administering to the subject oral octreotide; and

(b) counseling the subject to avoid concomitant use of a combined oralcontraceptive.

The inventors of the present invention have discovered a method ofadministering oral octreotide to a female subject in need thereofwherein said subject is using a combined oral contraceptive, comprising

(a) administering to the subject oral octreotide; and

(b) counseling the subject to use a back-up method of contraception orto use an alternative non-hormonal method of contraception.

Moreover, it is to be understood that both the foregoing information andthe following detailed description are merely illustrative examples ofvarious aspects and embodiments, and are intended to provide an overviewor framework for understanding the nature and character of the claimedaspects and embodiments. The accompanying drawings are included toprovide illustration and a further understanding of the various aspectsand embodiments and are incorporated in and constitute a part of thisspecification. The drawings, together with the remainder of thespecification, explain principles and operations of the described andclaimed aspects and embodiments.

Throughout this application, various publications, including UnitedStates patents, are referenced by author and year and patents andapplications by number. The disclosures of these publications andpatents and patent applications in their entireties are herebyincorporated by reference into this application in order to more fullydescribe the state of the art to which this invention pertains.

BRIEF DESCRIPTION OF THE DRAWINGS

Various aspects of at least one embodiment are discussed below withreference to the accompanying Figures. The Figures are provided for thepurposes of illustration and explanation and are not intended as adefinition of the limits of the invention. The Figures are as referencedin the accompanying Example.

In the Figures:

FIG. 1 presents pharmacokinetic data of R-warfarin with placebo and withoral octreotide;

FIG. 2 presents pharmacokinetic data of S-warfarin with placebo and withoral octreotide;

FIG. 3 presents pharmacokinetic data of hydrochlorothiazide (HCTZ) withplacebo and with oral octreotide;

FIG. 4 presents pharmacokinetic data of metformin with placebo and withoral octreotide;

FIG. 5 presents pharmacokinetic data of ethyl estradiol with placebo andwith oral octreotide; and

FIG. 6 presents pharmacokinetic data of norgestrel (levonorgestrel) withplacebo and with oral octreotide.

DETAILED DESCRIPTION OF THE INVENTION

Octreotide is a synthetic octapeptide analog of human somatostatin, anaturally occurring tetradecapeptide. Octreotide has been approved forchronic use in acromegaly patients as a life-long treatment by the FDAsince 1988 as Sandostatin®, produced by Novartis. Long acting depotoctreotide, octreotide LAR (Sandostatin LAR) was approved by the FDA in1998 for the treatment of acromegaly and diarrhea associated withcarcinoid syndrome and with vasoactive intestinal peptide secretingadenomas. Both forms of octreotide are administered parenterally sincein the past octreotide acetate when given orally had insufficientbioavailability.

Identifying the need for a less difficult (less cumbersome) alternativeto the currently available octreotide injections, Chiasma, Inc developeda new formulation of octreotide acetate for oral delivery utilizing itsproprietary Transient Permeability Enhancer (TPE®), and the product iscalled MYCAPSSA®. See for example co-assigned U.S. Pat. Nos. 8,535,695and 10,695,397.

MYCAPSSA is a delayed-release capsule which enables the oral delivery ofoctreotide acetate. MYCAPSSA was approved by the FDA on 26 Jun. 2020 forlong-term maintenance treatment in acromegaly patients who haveresponded to and tolerated treatment with octreotide or lanreotide.

MYCAPSSA (octreotide) delayed-release capsule is a combination ofoctreotide acetate and excipients collectively called TransientPermeability Enhancer (TPE®). TPE is a proprietary excipient mixturethat permits oral administration, comprised of the following:polyvinylpyrrolidone (PVP-12), sodium caprylate (octanoate), magnesiumchloride, polysorbate 80, glyceryl monocaprylate and glyceryltricaprylate.

TPE improves the oral bioavailability of poorly absorbed drugs such asoctreotide by increasing the permeability of the intestine. The mode ofaction of TPE is thought to involve a transient opening of the tightjunctions between epithelial cells lining the intestine. See Tuvia(2014) Pharm Res 31:2010-2021.

Oral octreotide acetate (herein also termed oral octreotide; the termsare used interchangeably herein) is supplied in an enteric-coatedcapsule filled with an oily suspension of octreotide acetate formulatedwith TPE. The enteric coating allows the intact capsule to pass throughthe stomach and disintegrate when it reaches the higher pH of the smallintestine to discharge oral octreotide acetate suspension.

The TPE facilitates intestinal absorbance of drug molecules with limitedintestinal bioavailability. Without being bound by theory, the TPEformulation protects the drug molecule from inactivation by the hostilegastrointestinal (GI) environment and at the same time acts on the GIwall to induce a transient and reversible opening of the paracellularroute allowing permeation of the drug molecules through the tightjunctions. These two attributes ensure that when delivered in TPEformulation, the drug reaches the bloodstream effectively in its nativeactive form. TPE is a combination of excipients assembled in a processleading to an oily suspension of hydrophilic particles containingmedium-chain fatty acid salts and the active pharmaceutical ingredient(API) suspended in a lipophilic medium.

The permeation enhancement effect of the TPE formulation in oraloctreotide acetate might affect the bioavailability of other orallyadministered drugs commonly used by acromegaly patients. Therefore, thepotential for drug-drug interaction (DDI) of oral octreotide acetatewith oral representative probe drugs was evaluated in this study. Probedrugs with the following specific characterizations were included: (i)drugs with low permeability such as metformin and HCTZ, and (ii) drugswith a narrow therapeutic window such as warfarin andlevonorgestrel/ethinyl estradiol.

This invention is directed to a method of administering oral octreotideto a female subject in need thereof wherein said subject is also in needof a contraceptive method, comprising

(a) administering to the subject oral octreotide; and

(b) counseling the subject to avoid concomitant use of a combined oralcontraceptive.

Efficacy of combination oral contraceptives comprising ethinyl estradioland levonorgestrel may be compromised when administered with oraloctreotide; alternative contraception may be recommended, e.g., abarrier method.

In an embodiment of the invention the combined oral contraceptivecomprises levonorgestrel.

This invention is directed to a method of administering oral octreotideto a female subject in need thereof wherein said subject is also in needof a contraceptive method, comprising

(a) administering to the subject a therapeutically effective amount oforal octreotide; and

(b) counseling the subject to avoid concomitant use of a combined oralcontraceptive.

Efficacy of combination oral contraceptives comprising ethinyl estradioland levonorgestrel may be compromised when administered with oraloctreotide; alternative contraception may be recommended, e.g., abarrier method.

In an embodiment of the invention, the combined oral contraceptivecomprises levonorgestrel.

This invention is also directed to a method of administering oraloctreotide to a female subject in need thereof wherein said subject isusing a combined oral contraceptive, comprising

(a) administering to the subject oral octreotide; and

(b) counseling the subject to use a back-up method of contraception orto use an alternative non-hormonal method of contraception.

This invention is also directed to a method of administering oraloctreotide to a female subject in need thereof wherein said subject isusing a combined oral contraceptive, comprising

(a) administering to the subject a therapeutically effective amount oforal octreotide; and

(b) counseling the subject to use a back-up method of contraception orto use an alternative non-hormonal method of contraception.

This invention is also directed to a method of administering oraloctreotide to a female subject in need thereof wherein said subject isusing a combined oral contraceptive, comprising

(a) administering to the subject oral octreotide; and

(b) counseling the subject to use a back-up method of contraception.

In an embodiment of the invention the combined oral contraceptivecomprises levonorgestrel.

This invention is also directed to a method of administering oraloctreotide to a female subject in need thereof wherein said subject isusing a combined oral contraceptive, comprising

(a) administering to the subject a therapeutically effective amount oforal octreotide; and

(b) counseling the subject to use a back-up method of contraception.

In an embodiment of the invention the combined oral contraceptivecomprises levonorgestrel.

This invention is also directed to a method of administering oraloctreotide to a female subject in need thereof wherein said subject isusing a combined oral contraceptive, comprising

(a) administering to the subject oral octreotide; and

(b) counseling the subject to use an alternative non-hormonal method ofcontraception.

This invention is also directed to a method of administering oraloctreotide to a female subject in need thereof wherein said subject isusing a combined oral contraceptive, comprising

(a) administering to the subject a therapeutically effective amount oforal octreotide; and

(b) counseling the subject to use an alternative non-hormonal method ofcontraception.

This invention is also directed to a method of treating a disease ordisorder described herein, the method comprising administering oraloctreotide to a female subject in need thereof wherein said subject isalso in need of a contraceptive method, comprising

(a) administering to the subject oral octreotide; and

(b) counseling the subject to avoid concomitant use of a combined oralcontraceptive.

This invention is also directed to a method of treating a disease ordisorder described herein, the method comprising administering oraloctreotide to a female subject in need thereof wherein said subject isalso in need of a contraceptive method, comprising

(a) administering to the subject a therapeutically effective amount oforal octreotide; and

(b) counseling the subject to avoid concomitant use of a combined oralcontraceptive.

In an embodiment of the invention the combined oral contraceptivecomprises levonorgestrel.

In a certain embodiment of the invention the subject has acromegaly; inanother embodiment of the invention the subject has severe diarrhea orflushing episodes associated with metastatic carcinoid tumor.

This invention is also directed to a method of administering oraloctreotide to a female subject in need thereof wherein said subject isalso in need of a contraceptive method, comprising

(a) administering to the subject oral octreotide; and

(b) counseling the subject to avoid (or discontinue) concomitant use ofa contraceptive which comprises levonorgestrel or to use a back-upmethod of contraception or to use an alternative method ofcontraception.

This invention is also directed to a method of administering oraloctreotide to a female subject in need thereof wherein said subject isalso in need of a contraceptive method, comprising

(a) administering to the subject a therapeutically effective amount oforal octreotide; and

(b) counseling the subject to avoid (or discontinue) concomitant use ofa combined oral contraceptive which comprises levonorgestrel or to use aback-up method of contraception or to use an alternative method ofcontraception.

In an embodiment of the invention the combined oral contraceptivecomprises levonorgestrel.

The term “therapeutically effective amount,” as used herein, refers toan amount of a compound sufficient to treat, ameliorate, or prevent theidentified disease or condition, or to exhibit a detectable therapeutic,prophylactic, or inhibitory effect. The effect can be detected by, forexample, an improvement in clinical condition, or reduction in symptoms.The precise effective amount for a subject will depend upon thesubject's body weight, size, and health; the nature and extent of thecondition; and the therapeutic or combination of therapeutics selectedfor administration.

As used herein, a subject “in need of oral octreotide therapy” is asubject who would benefit from administration of oral octreotide. Thesubject may be suffering from any disease or condition for which oraloctreotide therapy may be useful in ameliorating symptoms. Such diseasesor conditions include acromegaly, abnormal GI motility, carcinoidsyndrome, flushing associated with carcinoid syndrome or flushingassociated with a metastatic carcinoid tumor, diarrhea associated withcarcinoid syndrome in particular severe diarrhea, intractable or severediarrhea, portal hypertension, a neuroendocrine tumor, a vasoactiveintestinal peptide secreting adenoma, diarrhea associated with avasoactive intestinal peptide secreting adenoma in particular severediarrhea, flushing associated with a vasoactive intestinal peptidesecreting adenoma, gastroparesis, diarrhea, pancreatic leak orpancreatic pseudo-cysts or portal hypertension polycystic disease e.g.,polycystic kidney disease or polycystic liver disease or PCOS orhypotension especially neurogenic orthostatic hypotension andpostprandial hypotension.

The subject may need oral octreotide to prevent variceal bleeding e.g.,bleeding varices such as bleeding esophageal varices or bleeding gastricvarices.

Oral octreotide is indicated for symptomatic treatment of patients withmetastatic carcinoid tumors where it suppresses or inhibits the severediarrhea and flushing episodes associated with the disease.

As used herein, a subject “in need of a contraceptive method” is asubject who would benefit from administration of a contraceptive method(i.e., contraception or contraceptive therapy or birth control).Contraception (birth control) allows the subject to lower significantlythe chance of pregnancy. The use of contraception helps the subject todetermine how many children she may want to have as well as the timingof her pregnancies. The subject can then have a sexual relationship withgreatly reduced fear of an unwanted pregnancy.

As used herein, the term “avoid” and forms thereof are contemplated tohave as alternatives the terms abstain, desist, forbear, and refrain,and forms thereof. As used herein, the term “discontinue” and formsthereof are contemplated to have as alternatives the terms cease, stop,suspend, and quit.

The terms “concomitant,” “co-administration” and “co-administering” andtheir grammatical equivalents, as used herein, encompass administrationof two or more agents to the subject so that both agents and/or theirmetabolites are present in the subject at the same or substantially thesame time. The second agent may have been administered to the patientsubsequently, simultaneously, or prior to the administration of thefirst agent.

Combined hormonal contraceptives comprise of an estrogen and aprogestogen; these are synthetic versions (analogs or agonists) of thefemale hormones estrogen and progesterone which are produced naturallyin the ovaries. These synthetic hormones act primarily by preventingovulation through the inhibition of the follicle-stimulating hormone andluteinizing hormone. The progestogen component also renders the cervicalmucus relatively impenetrable to sperm and reduces the receptivity ofthe endometrium to implantation.

The combined oral contraceptive pill (COCP), often referred to as thebirth control pill or colloquially as “the pill”, is a type of birthcontrol that is designed to be taken orally by women. It includes acombination of an estrogen (usually ethinyl estradiol) and a progestogen(e.g., levonorgestrel). When taken correctly, it alters the menstrualcycle to eliminate ovulation and prevent pregnancy.

Oral, intravaginal, injectable and transdermal (patch)estrogen-progestogen combinations are used for the prevention ofconception in women.

A short-course, high-dose regimen of an oral estrogen-progestogencombination is used in women for the prevention of conception afterunprotected intercourse (postcoital contraception, “morning-after”pills) as an emergency contraceptive.

Reference: FSRH Guideline Combined Hormonal Contraception—Copyright ©Faculty of Sexual & Reproductive Healthcare January 2019.

Levonorgestrel is a progestogen (sometimes called a progestin). It is ahormonal medication which is used in a number of birth control methods.As described above, it is combined with an estrogen (usually ethinylestradiol) to produce combination birth control pills. Levonorgestrel isused in emergency contraceptive pills (ECPs), both in a combined Yuzpe®regimen which includes estrogen, and as a levonorgestrel-only method. Asan emergency birth control (“morning-after” pill), it is sold under thebrand name Plan B® among others, and it is useful within 120 hours ofunprotected sex. In an intrauterine device (IUD) or intrauterine system(IUS), such as Mirena® or Liletta® among others, levonorgestrel usedalone is effective for the long-term prevention of pregnancy. Alevonorgestrel-releasing implant is also available in some countries,sold under the brand name Jadelle® among others; this device releaseslevonorgestrel for birth control. The device is placed under the skinand lasts for up to five years.

Levonorgestrel works primarily by preventing ovulation and closing offthe cervix by causing changes in the cervical mucus to prevent thepassage of sperm. Levonorgestrel is used alone in some progestogen-onlypill formulations.

Avoiding, Discontinuing or Contraindicating Administration of a CombinedOral Contraceptive.

In some aspects, the invention provides a method of administering oraloctreotide therapy to a patient in need of oral octreotide therapy ororal octreotide for use in treating a patient in need of oral octreotidetherapy (e.g., a patient with acromegaly or suffering from severediarrhea or flushing episodes associated with metastatic carcinoidtumor) comprising administering to the patient a therapeuticallyeffective amount of oral octreotide, and avoiding use or administration(e.g., concomitant use or co-administration) of a combined oralcontraceptive. In some embodiments, the patient is advised to avoid useof a contraceptive method which comprises levonorgestrel and to use analternative non-hormonal method of contraception or to use a back-upnon-hormonal method of contraception.

In one example, in a method of administering a therapeutically effectiveamount of oral octreotide to a patient with acromegaly, or oraloctreotide for use in treating a patient in need of oral octreotidetherapy, the invention provides an improvement that comprises avoidingor discontinuing administration (e.g., concomitant use orco-administration) of a combined oral contraceptive and administering anon-hormonal method of contraception.

In some embodiments, the combined oral contraceptive is discontinuedconcurrent with starting administration of oral octreotide. In certainembodiments, the combined oral contraceptive is replaced with anothercontraceptive method. In other embodiments, the combined oralcontraceptive is discontinued within at least 3 days prior to startingoral octreotide therapy. In another embodiment, the combined oralcontraceptive is discontinued within 3 days after starting oraloctreotide therapy. Adequate time may be needed to counsel (advise) thepatient in using a back-up method of contraception or using analternative non-hormonal method of contraception.

Unlike other long-term medications, there is generally no need to taperoff hormonal birth control and it is considered safe to terminatetreatment (e.g., to stop taking the combined oral contraceptivemedication) at any time. To lower the chance of the patient gettingpregnant, a gap between methods should be avoided. The patient should gostraight from one contraceptive method to the next, with no gaps betweenmethods. This should preferably take place before beginning oraloctreotide therapy or within a few days e.g., within 3-5 days ofcommencing oral octreotide therapy.

Selecting an Alternative Contraceptive Drug or Therapy to AdministerConcurrently with Oral Octreotide Therapy

In some aspects, the invention provides a method of administering oraloctreotide therapy to a patient in need of oral octreotide therapy andalso in need of contraception by advising use of a contraceptive methodwhich is a non-hormonal method or which is not based on combined oralcontraceptives. Various types of non-hormonal methods of contraceptionare available and are described below.

In some embodiments, the patient is advised that co-administration oforal octreotide with a combined oral contraceptive can alter thetherapeutic effect of the combined oral contraceptive (e.g., can reducebioavailability of the combined oral contraceptive). In someembodiments, the patient is advised that administration of oraloctreotide and combined oral contraceptive can alter the therapeuticeffect of the combined oral contraceptive (e.g., can reduce exposure tocombined oral contraceptive).

In some embodiments, the patient is advised that she should avoidconcomitant use of oral octreotide with an oral contraceptive whichcomprises levonorgestrel (in order to avoid an unwanted pregnancy).

Backup Method of Contraception

Backup method of contraception is the use of secondary contraception inthe event of failure of or suboptimal primary contraception.

See Segen's Medical Dictionary. © 2012 Farlex, Inc. All rights reserved.

In embodiments of this invention the following non-hormonal methods ofcontraception methods can be considered to be back-up methods ofcontraception in addition to using a combined oral contraceptive. Inparticular, Numbers 1-6 and 8 can be considered to be back-up methods ofcontraception. Number 7, sterilization, is normally used alone as analternative method of contraception and not as a back-up.

In one of the embodiments of this invention, a back-up method is usedsince the combined oral contraceptive may give suboptimal contraceptiveprotection to a woman also receiving (being administered) oraloctreotide (and failure may be anticipated).

Additionally, each of the following non-hormonal methods ofcontraception methods can be considered an alternative method ofcontraception to combined oral contraceptives (and in fact to anyhormonal contraception).

Non-Hormonal Methods of Contraception.

Non-hormonal methods do not employ hormones such as estrogens orprogestogens.

There are at least nine types of hormone-free birth control options asdescribed below. See TOM (Institute of Medicine), A Review of the HHSFamily Planning Program: Mission, Management, and Measurement ofResults. Washington, DC: The National Academies Press. 2009.

Barrier Methods

Barrier methods of birth control prevent sperm from entering the uterus.These methods are used only during sexual intercourse and should be usedcorrectly every time two people have sex.

1. Diaphragm: The diaphragm is a small, flexible cup made of silicone. Awoman inserts the diaphragm into her vagina so that it covers thecervix. It is essential to put spermicide on the diaphragm and along itsedges before inserting it.

2. Cervical cap: The cervical cap is like the diaphragm but smaller.Women should always use spermicidal gel with the cervical cap to ensureits protective qualities

3. Spermicides: Spermicides are placed in the vagina before sexualintercourse to stop sperm from entering the uterus. They are availablein creams, gels, and suppositories. Spermicides have a failure rate of28 percent, this according to the American Pregnancy Association.However, when used with other methods, such as the diaphragm or cervicalcap, effectiveness increases.4. Male and female condoms: Condoms can help to prevent the spread ofSTI's, unlike other forms of non-hormonal birth control. However, theyare not the most effective form of birth control. The male latex condomis the best way to guard against STDs. It is also effective inpreventing pregnancy by keeping semen from entering the vagina. Thefemale condom is a strong, thin protective covering with a ring on eachside to hold it in place. It can protect against pregnancy and STDs.5. The sponge: The sponge is made of plastic foam and containsspermicide. A woman inserts it into her vagina before sexual intercourseand has a nylon loop for easy removal afterward. It is available at mostdrug stores and does not require a prescription. The sponge preventspregnancy by covering the cervix so that no sperm can enter. It alsoreleases spermicide to immobilize sperm. Each sponge can only be usedonce.Long-Term and Permanent Solutions

There are some long-term and permanent non-hormonal options that aresafe and effective for most healthy women.

6. Non-hormonal (copper) intrauterine device (IUD): A coppernon-hormonal intrauterine device (IUD) can work for up to 10 years. Inthe U.S., this non-hormonal intrauterine device (IUD) is available forexample under the brand name ParaGard®. It takes only a few minutes fora doctor to insert the device into the uterus. Once in place, the thincopper wire releases small amounts of copper to prevent sperm frompassing through the cervix. The ParaGard® is a good option for women whodo not want to worry about daily or weekly birth control birth remindersor do not want to use hormonal birth control. This method is completelyreversible and can be removed by a doctor at any time if a woman decidesshe wants to get pregnant.7. Sterilization: For people who want a permanent birth control method,sterilization may involve surgery that is difficult to reverse. Forwomen, the surgical procedure is a tubal ligation, and for men,vasectomy surgery provides permanent sterilization.Other Methods8. Withdrawal methodThe withdrawal method is the oldest form of birth control, but it is notthe most effective.9. Rhythm method (also called fertility awareness method).Package Insert Instructions

In one aspect of the invention, a package or kit is provided comprisingcapsules of oral octreotide, and a package insert, package label,instructions or other labeling including any one, two, three or more ofthe following information or recommendations: (a) advising a femalepatient that, when administered oral octreotide, a non-hormonal methodof contraception should be used; (b) advising a female patient that,when administered oral octreotide, an alternative method to a method ofcontraception comprising levonorgestrel should be used; (c) advising afemale patient that, when administered oral octreotide, use of combinedoral contraceptive should be avoided or a back-up method ofcontraception should be used; (d) advising a female patient thatadministration of levonorgestrel in patients administered oraloctreotide results in about a 24% decrease in levonorgestrel exposurecompared to women that are not administered oral octreotide; and (e)advising a female patient that a lack of contraceptive efficacy mayresult due to the potential for oral octreotide to reducebioavailability (absorption) of levonorgestrel.

In some embodiments, the information or recommendation may include thatco-administration of oral octreotide with levonorgestrel can alter thetherapeutic effect (e.g., can reduce bioavailability of levonorgestrel).In other embodiments, the information or recommendation may include thatadministration of oral octreotide to a patient who is being treated withoral contraceptives can alter the therapeutic effect of the oralcontraceptive (e.g., can reduce exposure to the oral contraceptive). Inother embodiments, the information or recommendation may include thatco-administration of oral octreotide with a combined oral contraceptivecan alter the bioavailability of the levonorgestrel in the combined oralcontraceptive (e.g., can reduce exposure to the levonorgestrel in thecombined oral contraceptive).

In other embodiments, the information or recommendation may include thatcombined oral contraceptives should be avoided and other methods ofcontraception should be used. In other embodiments, the information orrecommendation may include that hormonal methods of contraception shouldbe discontinued, and non-hormonal methods of contraception should beused. In other embodiments, the information or recommendation mayinclude that a combined oral contraceptive should not be used alone, andanother non-hormonal method of contraception should be used as a back-upmethod. In other embodiments, the information or recommendation mayinclude that a hormonal method of contraception should not be usedalone, and a non-hormonal method of contraception should be used as aback-up method.

In a related aspect, the invention provides a method of preparing orpackaging an oral octreotide medicament comprising packaging capsules oforal octreotide together with a package insert or package label orinstructions including any one, two, three or more of the foregoinginformation or recommendations.

The package insert, package label, instructions or other labeling mayfurther comprise directions for treating a patient suffering fromacromegaly or suffering from severe diarrhea or flushing episodesassociated with metastatic carcinoid tumor by administering oraloctreotide, e.g., at a dosage of between 20 to 200 mg per day (daily).Dosages envisaged are 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120,130, 140, 150, 160, 170, 180, 190 or 200 mg per day. These dosages maybe divided and administered once per day or twice per day or three timesper day.

In some embodiments of the invention the oral octreotide is administeredin capsules. The capsule may contain 5-50 mg octreotide in particular5-30 mg octreotide. The amount of octreotide which may be in eachcapsule are 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20,21, 22, 23, 24, 25, 30, 35, 40, 45 or 50 mg per capsule. In a particularembodiment there is 20 mg octreotide per capsule. In another particularembodiment there is 10 mg per octreotide capsule. In other embodimentsthere is 7-15 mg octreotide per capsule, e.g., 7, 8, 9, 10 11, 12, 13,14 or 15 mg per capsule.

The octreotide capsule described herein (e.g., MYCAPSSA) is an oralproduct indicated for long-term maintenance therapy in acromegalypatients; in certain embodiments the patients are those in whom priortreatment with somatostatin analogs (by injection) has been shown to beeffective and tolerated. The goal of treatment in acromegaly is tocontrol GH and IGF-1 levels and to lower the GH and IGF-1 levels to asclose to normal as possible.

Preferably the oral octreotide capsule should be administered with aglass of water on an empty stomach (i.e., at least 1 hour prior to ameal or at least 2 hours after a meal. In particular embodiments of allinventions described herein, a meal comprises 100-1000 calories, or300-600 calories which may be a high-fat meal or a high calorie meal andmay comprise carbohydrates and/or fat and or protein e.g., 100, 200,300, 400 calories or 500-1000 calories or 700-800 calories.

Patients currently receiving somatostatin analog therapy by injectioncan be switched to octreotide capsules with an initial dose of 40 mgoctreotide daily (e.g., 20 mg BID) given orally. Blood levels of IGF-1and clinical symptoms should be monitored. If IGF-1 is normal andclinical symptoms are controlled or response level (biochemical andsymptomatic response) is maintained, maintain oral octreotide dosage at40 mg octreotide daily (e.g., 20 mg BID). Dosage may be adjusted to 60mg daily (e.g., 40 mg morning+20 mg evening) if IGF-1 levels areincreased, as determined by the treating physician, or in case ofsymptomatic exacerbation. Monitoring is continued, while applying theabove algorithm for maintaining or increasing the dose up to 80 mgoctreotide daily (e.g., 40 mg BID). The administering throughout occursat least 2 hours after a meal, or at least 1 hour before a meal.

Additionally, if a capsule containing about 30 mg octreotide isadministered, then the above algorithm is used to adjust the dose from60 mg daily to 90 mg daily and a maximum of 120 mg daily; wherein theadministering occurs at least 2 hours after a meal, or at least 1 hourbefore a meal. In another embodiment, if a capsule containing about 30mg octreotide is administered, then the above algorithm is used toadjust the dose from 30 mg daily (only one capsule taken) to 60 mg dailyto 90 mg daily and a maximum of 120 mg daily; wherein the administeringoccurs at least 2 hours after a meal, or at least 1 hour before a meal.

Furthermore, if a capsule containing less than 20 mg octreotide isadministered e.g., 10 mg, then the above algorithm is adjustedconcomitantly. For example in an embodiment of the invention, if acapsule containing about 10 mg octreotide is administered, then theabove algorithm is used to adjust the dose from 20 mg daily to 30 mgdaily and a maximum of 60 mg daily as needed; wherein the administeringoccurs at least 2 hours after a meal, or at least 1 hour before a meal.

The invention may be used in the treatment of naïve patients or patientsalready treated with parenteral injections.

Patients who are not adequately controlled following dose titration canreturn to therapy by injections at any time. Proton pump inhibitors(PPIs), H2-receptor antagonists, and antacids may lead to a higherdosing requirement of oral octreotide to achieve therapeutic levels.

The invention may be used in the treatment of acromegaly in a subject,the method comprising orally administering to the subject at least oncedaily at least one dosage form comprising an oily suspension comprisingoctreotide, wherein the octreotide in each dosage form is from about 5mg to about 35 mg (e.g., 5, 10, 15, 20, 25, 30 or 35 mg), and whereinthe administering occurs at least 1 hour before a meal or at least 2hours after a meal, to thereby treat the subject. Another embodiment ofthe invention is a method of treating acromegaly in a subject, themethod comprising orally administering to the subject at least oncedaily at least one dosage form comprising an oily suspension comprisingoctreotide, wherein the octreotide in each dosage form is from about 18mg to about 22 mg, and wherein the administering occurs at least 1 hourbefore a meal or at least 2 hours after a meal to thereby treat thesubject.

A dosage form is essentially a pharmaceutical product in the form inwhich it is marketed for use, typically involving a mixture of activedrug components and nondrug components (excipients), along with othernon-reusable material that may not be considered either ingredient orpackaging (such as a capsule shell, for example).

The oily suspension as used herein comprises an admixture of ahydrophobic medium (lipophilic fraction) and a solid form (hydrophilicfraction) wherein the solid form comprises a octreotide and at least onesalt of a medium chain fatty acid, and wherein the medium chain fattyacid salt is present in the composition at an amount of 10% or more byweight such as 11%-15%, or 11%, 12%, 13%, 14%, 15% or more by weight.

Oral formulations of octreotide, comprising the oily suspensionincorporated in a capsule, have been described and claimed, for examplein co-assigned U.S. Pat. No. 8,329,198, which is hereby incorporated byreference.

Certain embodiments of the invention include a capsule containing acomposition comprising a suspension which comprises an admixture of ahydrophobic oily medium and a solid form wherein the solid formcomprises a therapeutically effective amount of octreotide, at least onesalt of a medium chain fatty acid and polyvinylpyrrolidone (PVP),wherein the polyvinylpyrrolidone is present in the composition at anamount of 3% or more by weight, and wherein the at least one salt of amedium chain fatty acid is present in the composition at an amount of atleast 10% by weight.

Certain embodiments of the invention include a capsule containing acomposition comprising a suspension which comprises an admixture of ahydrophobic oily medium and a solid form wherein the solid formcomprises a therapeutically effective amount of octreotide, at least onesalt of a medium chain fatty acid and polyvinylpyrrolidone (PVP),wherein the polyvinylpyrrolidone is present in the composition at anamount of 3% or more by weight, and wherein the at least one salt of amedium chain fatty acid is present in the composition at an amount of atleast 10% by weight or at least 12% by weight.

In further embodiments the polyvinylpyrrolidone is present in thecomposition at an amount of about 5% to about 15% by weight and/or thepolyvinylpyrrolidone has a molecular weight of about 3000; and/or themedium chain fatty acid salt has a chain length from about 6 to about 14carbon atoms and/or the medium chain fatty acid salt is sodiumhexanoate, sodium heptanoate, sodium octanoate, sodium nonanoate, sodiumdecanoate, sodium undecanoate, sodium dodecanoate, sodium tridecanoateor sodium tetradecanoate, or a corresponding potassium or lithium orammonium salt or a combination thereof. In a particular embodiment ofthe invention the medium chain fatty acid salt is sodium octanoateand/or the medium chain fatty acid salt is present in the capsule at anamount of 12% to 18% by weight.

In further embodiments the hydrophobic oily medium within the capsulecomprises a mineral oil, a paraffin, a fatty acid a monoglyceride, adiglyceride, a triglyceride, an ether or an ester, or a combinationthereof; in a particular embodiment the hydrophobic oily mediumcomprises glyceryl tricaprylate.

In further embodiments the medium chain fatty acid salt is a lithium,potassium or ammonium salt or is octanoic acid.

In some embodiments, the octreotide is octreotide acetate.

In a particular embodiment, the composition within the capsule furthercomprises a surfactant.

In a particular embodiment of the invention the composition within thecapsule comprises a therapeutically effective amount of octreotide andabout 12-21% of sodium octanoate, about 5-10% of polyvinylpyrrolidonewith a molecular weight of about 3000, about 20-80% of glyceryltricaprylate, about 0-50% castor oil, about 3-10% surfactant and about1% water.

In another embodiment of the invention the composition within thecapsule comprises a therapeutically effective amount of octreotide andabout 12-21% of sodium octanoate, about 5-10% of polyvinylpyrrolidonewith a molecular weight of about 3000, about 20-80% of glyceryltricaprylate, about 3-10% surfactant and about 1% water.

In another embodiment of the invention the encapsulated composition(composition within the capsule) comprises a therapeutically effectiveamount of octreotide wherein the octreotide is present at an amount ofless than 33%.

In a particular embodiment of the invention the encapsulated compositioncomprises about 15% of sodium octanoate, about 10% ofpolyvinylpyrrolidone with a molecular weight of about 3000, about 30-70%glyceryl tricaprylate and about 6% of surfactant e.g., glycerylmonocaprylate and/or polyoxyethylene sorbitan monooleate.

In a particular embodiment of the invention the solid form within theencapsulated composition the comprises a particle or a plurality ofparticles.

In another embodiment of the invention the solid form within theencapsulated composition comprises a stabilizer.

In particular embodiments of the invention the capsule is entericcoated.

In particular embodiments of the invention the octreotide is present inthe encapsulated composition at an amount of less than 25%, less than10%, less than 1%.

In a particular embodiment of the method of the invention the oilysuspension is formulated into a capsule, which may be entericallycoated. In another embodiment of the method of the invention the capsuleconsists of an oily suspension. In another embodiment of the method ofthe invention the subject is dosed every 8-16 hours (e.g., every 12hours). In another embodiment of the method of the invention oneadministration takes place at least 6, 8, 10 or 12 hours before a secondadministration. In a preferred embodiment the subject is a human.

For clarity, the twice daily administration comprises a firstadministration and a second administration. In a further embodiment afirst administration includes one or two dosage forms and a secondadministration includes one or two dosage forms, and more particularlythe first administration includes one dosage form and the secondadministration includes one dosage form, or the first administrationincludes two dosage forms and the second administration includes onedosage form, or the first administration includes two dosage forms andthe second administration includes two dosage forms. In embodiments ofthe invention the first administration is in the morning (normally 5 amto noon) and the second administration is in the evening (normally 5 pmto midnight). All the administering occurs at least 1 hour before a mealor at least 2 hours after a meal.

Particular embodiments of the invention are as follows: one dosage formis administered twice daily; two dosage forms are administered once aday and one dosage form is administered once a day; and two dosage formsare administered twice daily. Other embodiments of the invention are asfollows: one dosage form is administered once a day; two dosage formsare administered once a day; three or more dosage forms are administeredonce a day; and two or more dosage forms (e.g., three dosage forms) areadministered twice a day. All the administering occurs at least 1 hourbefore a meal or at least 2 hours after a meal.

In some embodiments of the invention, the administration may beself-administration; in other embodiments of the invention or acaregiver or health professional may administer the dosage form.

In certain embodiments of the invention each dosage form comprises fromabout 19 to about 21 mg of octreotide and in a particular embodiment ofthe invention each dosage form comprises 20 mg of octreotide which isabout 3% w/w octreotide or 3.3% w/w octreotide. In certain embodimentsof the invention the total amount of octreotide administered per day isfrom about 36 to about 44 mg (e.g., from about 38 to about 42 mg, or 40mg). In certain embodiments of the invention the total amount ofoctreotide administered per day is from about 54 to about 66 mg (e.g.,from about 57 to about 63 mg, or 60 mg). In certain embodiments of theinvention the total amount of octreotide administered per day is fromabout 72 to about 88 mg (e.g., from about 76 to about 84 mg, or 80 mg).In certain embodiments of the invention the total amount of octreotideadministered per day is from about 90 to about 110 mg (e.g., from about95 to about 105 mg, or 100 mg). All the administering occurs at least 1hour before a meal or at least 2 hours after a meal.

In certain embodiments of the invention each dosage form comprises fromabout 27 to about 33 mg of octreotide and in a particular embodiment ofthe invention each dosage form comprises 30 mg of octreotide which isabout 5% w/w octreotide or 4.96% w/w octreotide. This may beadministered as one, two, three or four capsules per day, whereinadministering occurs at least 1 hour before a meal or at least 2 hoursafter a meal.

In another embodiments of the invention each dosage form comprises lessthan 20 mg octreotide and in a particular embodiment of the inventioneach dosage form comprises about 10 mg. This may be administered as one,two, three or four capsules per day, wherein administering occurs atleast 1 hour before a meal or at least 2 hours after a meal.

In further embodiments, the method of the invention occurs over aduration of at least 7 months, occurs over a duration of at least 13months and over a duration of greater than 13 months. In a particularembodiment the method of treatment is for long-term maintenance therapy.Long-term maintenance therapy in a subject suffering from acromegalycontinues as long as the subject is suffering from acromegaly and theIGF-1 levels are maintained at equal or less than 1.3 times the upperlimit of the age-adjusted normal range (ULN). Thus the duration may beunlimited. In particular embodiments the long-term maintenance therapymay be for at least one, two, three, four or five years and more. In aparticular embodiment upon administration of octreotide, an_in vivoamount of growth hormone integrated over 2 hours is obtained which isequal or less than 2.5 ng/mL or equal or less than 1.0 ng/mL.

In further embodiments, upon administration of octreotide, an in vivoconcentration of IGF-I is obtained of equal or less than 1.3 times theupper limit of the age-adjusted normal range (ULN), or equal or lessthan 1.0 or 1.1 or 1.2 or 1.4 or 1.5 or 1.6 times the upper limit of theage-adjusted normal range (ULN).

In certain embodiments, an in vivo mean peak plasma concentration uponadministration of octreotide of about 3.5+/−0.5 ng/mL is achieved. Incertain embodiments an in vivo mean area under the curve uponadministration of octreotide is about 15+/−4 h×ng/mL is obtained. Inparticular embodiments of the method of the invention the subject hashad prior treatment for acromegaly, and the prior treatment foracromegaly was surgical and/or medicinal; in certain embodiments themedicinal treatment was a somatostatin analog (=somatostatin receptorligand) e.g., injectable octreotide or injectable lanreotide orinjectable pasireotide and/or a dopamine agonist e.g., cabergolineand/or a GH receptor antagonist e.g., pegvisomant.

In particular embodiments the prior treatment of the subject with asomatostatin analog has been shown to be effective and tolerated.

In particular embodiments the prior treatment of the subject produced anIGF-1 level in the subject of equal or less than 1.3 times upper limitof normal (ULN), and/or prior treatment of the subject produced 2-hourintegrated growth hormone (GH) of less than 2.5 ng/mL or less than 1.0ng/mL

Preferably the oral octreotide capsule should be administered on anempty stomach (i.e., at least 1 hour prior to a meal or at least 2 hoursafter a meal. In particular embodiments of all inventions describesherein, a meal comprises 100-1000 calories, or 300-600 calories whichmay be a high-fat meal or a high calorie meal and may comprisecarbohydrates and/or fat and or protein e.g., 100, 200, 300, 400calories or 500-1000 calories or 700-800 calories.

The invention also contemplates titrating a patient suffering fromacromegaly to determine the effective dose of octreotide. Such anembodiment of the invention relates to a method of titrating a patienthaving acromegaly, the method comprising orally administering to thesubject at least once daily (e.g., twice daily) at least one dosage formcomprising an oily suspension comprising octreotide, wherein theoctreotide in each dosage form is from about 18 mg to about 22 mg,wherein the total amount of octreotide administered per day is fromabout 36 to about 44 mg; and subsequent to the administration,evaluating an IGF-1 level (and/or a GH level) in a subject and comparingthe level to a reference standard; wherein if the IGF-1 level (and/orthe GH level) is above the reference standard, increasing the totalamount of octreotide administered per day to from about 54 to about 66mg; wherein the administering occurs at least 2 hours after a meal, orat least 1 hour before a meal.

Another such embodiment of the invention relates to a method oftitrating a patient having acromegaly, the method comprising orallyadministering to the subject at least once daily (e.g., twice daily) atleast one dosage form comprising an oily suspension comprisingoctreotide, wherein the octreotide in each dosage form is from about 18mg to about 22 mg, wherein the total amount of octreotide administeredper day is from about 54 to about 66 mg; and subsequent to theadministration, evaluating an IGF-1 level (and/or a GH level) in asubject and comparing the level to a reference standard; wherein if theIGF-1 level (and/or the GH level) is above the reference standard,increasing the total amount of octreotide administered per day to fromabout 72 to about 88 mg; wherein the administering occurs at least 2hours after a meal or at least 1 hour before a meal.

In one embodiment of the invention, if a capsule containing about 30 mgoctreotide is administered, then the above algorithm is used to adjustthe dose from 60 mg daily to 90 mg daily and a maximum of 120 mg daily;wherein the administering occurs at least 2 hours after a meal, or atleast 1 hour before a meal. In another embodiment, if a capsulecontaining about 30 mg octreotide is administered, then the abovealgorithm is used to adjust the dose from 30 mg daily (only one capsuletaken) to 60 mg daily (two capsules) to 90 mg daily (three capsules) anda maximum of 120 mg daily (four capsules); wherein the administeringoccurs at least 2 hours after a meal, or at least 1 hour before a meal.

In a further embodiment of the invention, if a capsule containing lessthan 20 mg octreotide is administered e.g., 10 mg, then the abovealgorithm is adjusted concomitantly. In further embodiments the capsulecoating and/or encapsulated formulation is adjusted (changed) to permitgreater bioavailability and then each capsule may contain less than 20mg octreotide. For example if the bioavailability is improved to becomesdouble the previous bioavailability, then only half the amount ofoctreotide is required per capsule i.e., 10 mg per capsule to achievethe same effect.

In further embodiments of the titrating invention the oily suspension isformulated into a capsule; the capsule is enterically coated; the oraladministration is twice daily comprising a first and secondadministration; the subject is dosed every 8-16 hours (e.g., every 12hours); one administration takes place at least 6, 8, 10 or 12 hoursbefore a second administration; and the subject is a human. In a furtherembodiment of the titrating invention the first administration prior toevaluation includes one or two dosage forms and the secondadministration includes one or two dosage forms. In a further embodimentof the titrating invention, the first daily administration prior toevaluation includes one dosage form and the second daily administrationprior to evaluation includes one dosage form. In a further embodiment ofthe titrating invention the first daily administration prior toevaluation includes two dosage forms and the second daily administrationprior to evaluation includes one dosage form. In a further embodiment ofthe titrating invention the first daily administration after evaluationincludes two dosage forms and the second daily administration afterevaluation includes two dosage forms. In a further embodiment of theinvention one dosage form is administered once a day and two dosageforms are administered once a day, prior to evaluation. In a furtherembodiment of the invention two dosage forms are administered twicedaily after evaluation. Administering occurs at least 2 hours after ameal, or at least 1 hour before a meal.

In a further embodiment of the invention each dosage form comprises fromabout 19 to about 21 mg of octreotide, more particularly 20 mg ofoctreotide which is about 3% w/w octreotide. In a further embodiment ofthe invention the total amount of octreotide administered per day priorto evaluation is from about 36 to about 44 mg (e.g., from about 38 toabout 42 mg, or 40 mg). In a further embodiment of the invention thetotal amount of octreotide administered per day prior to evaluation isfrom about 54 to about 66 mg (e.g., from about 57 to about 63 mg, or 60mg).

In a further embodiment of the invention the total amount of octreotideadministered per day subsequent to evaluation is from about 54 to about66 mg (e.g., from about 57 to about 63 mg, or 60 mg). In a furtherembodiment of the invention the total amount of octreotide administeredper day subsequent to evaluation is from about 72 to about 88 mg (e.g.,from about 76 to about 84 mg, or 80 mg). In a further embodiment of theinvention the evaluation takes place at least two months from start oftherapy (i.e., from start of administration of the dosage forms), 2-5months from start of therapy or after 5 months from start of therapy(e.g., after 5, 6, 7 or 8 months or more from start of therapy).

In a specific embodiment of the invention the blood levels of IGF-1 andclinical symptoms are monitored when oral octreotide capsule dosage at40 mg (20 mg BID), and if IGF-1 is normal and clinical symptoms arecontrolled or response level (biochemical and symptomatic response) ismaintained, then oral octreotide capsule dosage is continued at 40 mg(20 mg BID). In a further specific embodiment of the invention the bloodlevels of IGF-1 and clinical symptoms are further monitored when oraloctreotide capsule dosage is at 40 mg, and if IGF-1 is not normal andclinical symptoms are not controlled or response level (biochemical andsymptomatic response) is not maintained, then oral octreotide capsuledosage is increased to 60 mg daily (40 mg morning+20 mg evening). In afurther specific embodiment of the invention the blood levels of IGF-1and clinical symptoms are further monitored when oral octreotide capsuledosage is at 60 mg, and if IGF-1 is normal and clinical symptoms arecontrolled or response level (biochemical and symptomatic response) ismaintained, then oral octreotide capsule dosage is continued at 60 mgdaily. In a further specific embodiment of the invention the bloodlevels of IGF-1 and clinical symptoms are further monitored when oraloctreotide capsule dosage is at 60 mg, and if IGF-1 is not normal andclinical symptoms are not controlled or response level (biochemical andsymptomatic response) is not maintained, then oral octreotide capsuledosage is increased to 80 mg (40 mg morning+40 mg evening)

In a further embodiment of the invention the reference standard is an invivo amount of growth hormone integrated over 2 hours is obtained whichis equal or less than 2.5 ng/mL (for example equal or less than 1.0ng/mL). In a further embodiment of the invention the reference standardis an in vivo concentration of IGF-I is obtained of equal or less than1.3 times the upper limit of the age-adjusted normal range (ULN).

In a further embodiment of the invention an in vivo mean peak plasmaconcentration upon administration of octreotide after evaluation isabout 3.5+/−0.5 ng/mL. In a further embodiment of the invention an invivo mean area under the curve upon administration of octreotide afterevaluation is about 15+/−4 h×ng/mL. In a further embodiment of thetitrating invention the subject has had prior treatment for acromegalywhich was surgical and/or pharmaceutical e.g., the pharmaceuticaltreatment was a somatostatin receptor ligand e.g., octreotide orlanreotide and was administered by injection. In a further embodiment ofthe titrating invention prior treatment of the subject with asomatostatin analog has been shown to be effective and tolerated. In afurther embodiment of the invention the prior pharmaceutical treatmentwas pegvisomant or a dopamine agonist e.g., cabergoline.

In a further embodiment of the invention, prior treatment of the subjectproduced an IGF-1 level in the subject of equal or less than 1.0 to 1.5times upper limit of normal (ULN) e.g., equal or less than 1.3 timesupper limit of normal (ULN). In a further embodiment of the inventionprior treatment of the subject produced 2-hour integrated growth hormone(GH) of less than 2.5 ng/mL e.g., less than 1.0 ng/mL.

A further embodiment of the invention is a method of predictingsubsequent response to oral octreotide capsules in a patient receivinginjectable treatment. Thus an embodiment of the invention is a method ofpredicting subsequent response to oral octreotide capsules comprisingthe oily suspension in a patient suffering from acromegaly, the methodcomprising measuring the degree of baseline control on injectable SRLs;and thereby determining if the patient is likely to respond to the oraloctreotide capsules. In an embodiment of the invention the desiredbaseline control is IGF-I≤1ULN and GH<2.5 ng/mL when the patient ismaintained on low to mid doses of injectable SRLs (octreotide<30 mg orlanreotide<120 mg).

In a particular embodiment the octreotide is formulated in assignee'sproprietary formulation denoted as Transient Permeability Enhancer,TPE®. TPE is a combination of excipients assembled in a process leadingto an oily suspension of hydrophilic particles containing medium-chainfatty acid salts and the active pharmaceutical ingredient (hereinoctreotide) suspended in a lipophilic medium and incorporated into acapsule. See co-assigned U.S. Pat. No. 8,535,695, which is incorporatedby reference herein.

Dosages comprising octreotide should be not be administered with food.Dosages comprising octreotide should be administered preferably one hourbefore a meal or two hours after a meal i.e., on an empty stomach.

In some embodiments, a method of treating a patient suffering fromacromegaly or suffering from severe diarrhea or flushing episodesassociated with metastatic carcinoid tumor is disclosed comprisingproviding, selling or delivering any of the kits disclosed herein to ahospital, physician or patient.

The invention will be more fully understood by reference to thefollowing example which details an exemplary embodiment of theinvention. This example should not, however, be construed as limitingthe scope of the invention. All citations throughout the disclosure arehereby expressly incorporated by reference.

While the present invention has been described in terms of variousembodiments and examples, it is understood that variations andimprovements will occur to those skilled in the art.

EXAMPLE

A Single-Dose, Crossover Study to Investigate the Drug-Drug InteractionBetween Oral Octreotide and Four Probe Drugs, Warfarin,Hydrochlorothiazide, Metformin and Estradiol (fromlevonorgestrel/ethinyl estradiol), in Healthy Volunteers.

Objective: To evaluate the influence of oral octreotide acetate 40 mg(single dose of oral octreotide acetate 40 mg (2×20 mg capsules)) on theabsorption, pharmacokinetics (PK) and bioavailability of concomitantlyadministered oral probe drugs, warfarin, hydrochlorothiazide (HCTZ),metformin, and estradiol (from levonorgestrel/ethinyl estradiol) inhealthy subjects.

This was a single-center, randomized, single-blind, placebo-controlled,crossover design study in 20 healthy male and female subjects.

Eligible subjects were randomized in a 1:1 ratio to one of two treatmentsequences of test conditions (i.e., Group 1 or Group 2); females werestudied under 4 test conditions (A to D), whereas males were studiedunder 2 test conditions only (A and B), as shown in Table 1.

TABLE 1 Group 1 Group 2 Test conditions A* B* B* A* C** D** D** C** *7women and 3 men; **7 women Test Conditions: A: Oral octreotide +warfarin, HCTZ, and metformin B: placebo + warfarin, HCTZ, and metforminC: placebo + levonorgestrel/ethinyl estradiol D: Oral octreotide +levonorgestrel/ethinyl estradiol HCTZ = hydrochlorothiazide

The study comprised a screening period, 4 treatment (dosing) periods forfemales and 2 treatment periods for males, and a follow-up period(approximately 7-10 days following the last dosing). There was a washoutperiod of at least 14 days between dosing events.

Methods

The effect of oral octreotide (as MYCAPSSA product) on the absorption ofwarfarin, HCTZ, and metformin was assessed by comparing Test ConditionsA and B in up to 20 subjects (males and females). The effect of MYCAPSSAon the absorption of estradiol was assessed by comparing Test ConditionsC and D in up to 14 females. Timing of PK blood samples is presented inTable 2. Blood sampling was conducted over the first 5 hours afteradministration.

TABLE 2 Timing of Pharmacokinetic Blood Samples Test Analyte ConditionTiming of PK blood samples Octreotide A, B, 1 hr, 3 hr, and 5 hr postdose for each test C and D condition Warfarin, A and B 0 pre-dose (up to60 minutes before drug HTCZ, and administration), 15 min, 30 min, 45min, 1 hr, 1.5 metformin hr, 2 hr, 2.5 hr, 3 hr, 4 hr, and 5 hrpost-dose Estradiol C and D −12 hr (±20 minutes) (upon admission),pre-dose: at 70-60 minutes and 30 (±5) minutes before drugadministration, and at 15 min, 30 min, 45 min, 1 hr, 1.5 hr, 2 hr, 2.5hr, 3 hr, 4 hr, and 5 hr post-dose Test Conditions: A: oral octreotide +warfarin, HCTZ, and metformin B: placebo + warfarin, HCTZ, and metforminC: placebo + levonorgestrel/ethinyl estradiol D: oral octreotide +levonorgestrel/ethinyl estradiol HCTZ = hydrochlorothiazide; PK =pharmacokinetic

The PK parameters C_(max) and AUC₀₋₅ for R- and S-warfarin, HCTZ andmetformin (Test Conditions A and B) and norgestrel and ethinyl estradiol(Test Conditions C and D) were compared between treatments using anANOVA statistical model with treatment, period, sequence, and subjectwithin sequence as the classification variables, using the naturallogarithms of the data. Confidence intervals (CIs) (90%) wereconstructed for the geometric mean rations (GMRs) (probe drug+oraloctreotide to probe drug alone) of the 2 parameters using the naturallog-transformed data and the 2 one-sided t-tests procedure. The GMRs andCIs were exponentiated back to the original scale. The effect ofconcurrent administration of oral octreotide was assessed from the GMRsand 90% CIs. The discrete parameter T_(max) was compared amongtreatments using non-parametric analyses.

Results

Warfarin

R-Warfarin

FIG. 1 shows the mean±standard error plasma concentrations of R-Warfarinafter oral administration of single 7.5 mg doses of racemic warfarin tohealthy volunteers with a single 40 mg (2×20 mg) dose of oral octreotideacetate or with placebo. As illustrated in FIG. 1, the arithmetic meanplasma concentrations of R-warfarin were comparable after administrationwith oral octreotide and with placebo. The PK data of the individualsubjects showed that this was also observed for the majority of theindividual subjects. The arithmetic (Table 3) and geometric (Table 4)mean values for C_(max) and AUC_(0-5h) were comparable. The GMRs were101.84% and 105.17%, respectively, and the 90% CIs were contained within80.00% to 125.00% (Table 4) indicating no effect of oral octreotide onthe early exposure to R-warfarin.

TABLE 3 Summary of Pharmacokinetic Parameters for R-Warfarin after OralAdministration of Single 7.5-mg Doses of Racemic Warfarin to HealthyVolunteers With and Without a Single 40-mg (2 × 20 mg) Dose of OralOctreotide Acetate Oral Octreotide Parameter* With WithoutC_(max(ng/mL))   508 ± 97.0 (18)   498 ± 82.0 (18) T_(max(h)) 2.00 (18)1.00 (18) [0.50-5.00] [0.50-4.00] AUC₍₀₋₅₎ (h × ng/mL) 2012 ± 348 (18)1907 ± 280 (18) *Mean ± standard deviation (N) except T_(max) for whichthe median (N) [Range] is reported. AUC = area under the curve; C_(max)= maximum plasma concentration; T_(max) = time of maximum plasmaconcentration

TABLE 4 Statistical Comparison of Pharmacokinetic Parameters forR-Warfarin After Oral Administration of Single 7.5-mg Doses of RacemicWarfarin to Healthy Volunteers With and Without a Single 40-mg (2 × 20mg) Dose of Oral Octreotide Acetate Geometric Mean* Geometric Mean Ratio(%)^(†) Parameter Test Reference Estimate 90% Confidence IntervalR-Warfarin with oral octreotide vs R-Warfarin with Placebo C_(max)500.10 491.04 101.84 93.91 110.45 AUC₍₀₋₅₎ 1984.36 1886.85 105.17 99.62111.02 *Least squares geometric means. Based on analysis of naturallog-transformed pharmacokinetic parameters. ^(†)Lower confidenceinterval limits <80.00% and upper confidence interval limits >125.00%are shown in red. ‡Warfarin was co-administered with HCTZ and metformin.AUC = area under the curve; C_(max) = maximum plasma concentration; HCTZ= hydrochlorothiazideS-Warfarin

FIG. 2 shows the mean±standard error plasma concentrations of warfarinafter oral administration of single 7.5 mg doses of racemic warfarin tohealthy volunteers with a single 40 mg (2×20 mg) dose of oral octreotideacetate or with placebo.

As illustrated in FIG. 2 the arithmetic mean plasma concentrations ofS-warfarin were comparable after administration with oral octreotide andwith placebo. This was also observed for the majority of the individualsubjects. The arithmetic (Table 5) and geometric (Table 6) mean valuesfor C_(max) and AUC₀₋₅ were comparable. The GMRs were 97.06% and102.38%, respectively, and the 90% CIs were contained within 80.00% to125.00% (Table 6), indicating no effect of oral octreotide on theexposure to S-warfarin.

TABLE 5 Summary of Pharmacokinetic Parameters for S-Warfarin After OralAdministration of Single 7.5-mg Doses of Racemic Warfarin to HealthyVolunteers With and Without a Single 40-mg (2 × 20 mg) Dose of OralOctreotide Acetate Oral Octreotide Acetate Parameter* With WithoutC_(max(ng/mL))    492 ± 114.2 (18)   503 ± 91.2 (18) T_(max(h)) 1.50(18) 1.00 (18) [0.30-5.00] [0.50-4.00] AUC₍₀₋₅₎ (h × ng/mL) 1894 ± 330(18) 1846 ± 286 (18) *Mean ± standard deviation (N) except T_(max) forwhich the median (N) [Range] is reported. AUC = area under the curve;C_(max) = maximum plasma concentration; T_(max) = time of maximum plasmaconcentration

TABLE 6 Statistical Comparison of Pharmacokinetic Parameters for5-Warfarin After Oral Administration of Single 7.5 mg Doses of RacemicWarfarin to Healthy Volunteers With and Without a Single 40 mg (2 × 20mg) Dose of Oral Octreotide Acetate Geometric Mean* Geometric Mean Ratio(%)^(†) Parameter Test Reference Estimate 90% Confidence IntervalS-Warfarin with Oral Octreotide vs S-Warfarin with Placebo C_(max)480.09 494.64 97.06 88.49 → 106.46 AUC₍₀₋₅₎ 1867.56 1824.19 102.38 97.21→ 107.82 *Least squares geometric means. Based on analysis of naturallog-transformed pharmacokinetic parameters. ^(†)Lower confidenceinterval limits <80.00% and upper confidence interval limits >125.00%are shown in red. ‡Warfarin was co-administered with HCTZ and metformin.AUC = area under the curve; Cmax = maximum plasma concentration; HCTZ =hydrochlorothiazideHydrochlorothiazide (HCTZ)

The arithmetic mean plasma concentrations of HCTZ were lower afteradministration with oral octreotide acetate compared to placebo (FIG.3). FIG. 3 shows the mean±standard error plasma concentrations of HCTZafter oral administration of single 100 mg (4×25 mg) doses to healthyvolunteers with a single 40 mg (2×20 mg) dose of oral octreotide acetateor with placebo. As illustrated in FIG. 3, although there wasvariability in the pattern among the individual subjects, this wasobserved for the majority of subjects. The arithmetic (Table 7) andgeometric (Table 8) mean values for C_(max) and AUC₀₋₅ were lower duringconcomitant administration with oral octreotide acetate. The GMRs were91.21% and 81.82%, respectively (Table 8). The 90% CI for C_(max) wascontained within 80.00% to 125.00%, but that for AUC₀₋₅ was not (Table8). Although the median T_(max) was longer when HCTZ was administeredwith oral octreotide (4.00 vs 2.75 h), the ranges were comparable (Table7).

Overall, exposure to HCTZ is lower when administered with oraloctreotide.

TABLE 7 Summary of Pharmacokinetic Parameters for HydrochlorothiazideAfter Oral Administration of Single 100-mg (4 × 25 mg) Doses to HealthyVolunteers With and Without a Single 40-mg (2 × 20 mg) Dose of OralOctreotide Acetate Oral Octreotide Parameter* With WithoutC_(max(ng/mL))  602 ± 141 (18)  655 ± 128 (18) T_(max(h)) 4.00 (18) 2.75(18) [2.50-5.05] [2.00-5.00] AUC₍₀₋₅₎ (h × ng/mL) 1722 ± 537 (18) 2034 ±392 (18) *Mean ± standard deviation (N) except T_(max) for which themedian (N) [Range] is reported. AUC = area under the curve; C_(max) =maximum plasma concentration; T_(max) = time of maximum plasmaconcentration

TABLE 8 Statistical Comparison of Pharmacokinetic Parameters forHydrochlorothiazide After Oral Administration of Single 100-mg (4 × 25mg) Doses to Healthy Volunteers With and Without a Single 40-mg (2 × 20mg) Dose of Oral Octreotide Acetate Geometric Mean* Geometric Mean Ratio(%)† Parameter Test Reference Estimate 90% Confidence Interval HCTZ withoral octreotide vs HCTZ with Placebo C_(max) 586.50 643.03 91.21 81.77 →101.73 AUC₍₀₋₅₎ 1633.38 1996.30 81.82 70.97 → 94.33  *Least squaresgeometric means. Based on analysis of natural log-transformedpharmacokinetic parameters. †Lower confidence interval limits <80.00%and upper confidence interval limits >125.00% are shown in red. ‡HCTZwas co-administered with warfarin and metformin. AUC = area under thecurve; C_(max) = maximum plasma concentration; HCTZ =hydrochlorothiazideMetformin

FIG. 4 shows the mean±standard error plasma concentrations of metforminafter oral administration of single 850 mg to healthy volunteers with asingle 40 mg (2×20 mg) dose of oral octreotide acetate or with placebo.FIG. 4 illustrates that arithmetic mean plasma concentrations ofmetformin over the initial 5 hours showed a slower rate of absorptionwhen metformin was administered with oral octreotide (FIG. 4) ascompared to placebo, but the pattern varied among the individualsubjects.

The arithmetic (Table 9) and geometric (Table 10) mean values forC_(max) were higher during concomitant administration, while those forAUC₀₋₅ were lower (Table 9 and Table 10). The GMRs were 110.63% and95.28%, respectively, and the 90% CIs for both parameters were containedwithin 80.00% to 125.00, indicating no effect of oral octreotide on theearly exposure to metformin.

TABLE 9 Summary of Pharmacokinetic Parameters for Metformin After OralAdministration of Single 850-mg Doses to Healthy Volunteers With andWithout a Single 40-mg (2 × 20 mg) Dose of Oral Octreotide Acetate OralOctreotide Parameter* With Without C_(max(ng/mL)) 1566 ± 242 (18) 1450 ±398 (18)  T_(max(h)) 5.00 (18) 3.00 (18) [1.00-5.05] [1.00-5.00]AUC₍₀₋₅₎ (h × ng/mL) 5165 ± 840 (18) 5502 ± 1276 (18) *Mean ± standarddeviation (N) except T_(max) for which the median (N) [Range]isreported. AUC = area under the curve; C_(max) = maximum plasmaconcentration; T_(max) = time of maximum plasma concentration

TABLE 10 Statistical Comparison of Pharmacokinetic Parameters forMetformin After Oral Administration of Single 850-mg Doses to HealthyVolunteers With and Without a Single 40-mg (2 × 20 mg) Dose of OralOctreotide Acetate Geometric Mean* Geometric Mean Ratio (%)^(†)Parameter Test Reference Estimate 90% Confidence Interval Metformin withoral octreotide vs Metformin with Placebo C_(max) 1547.78 1399.01 110.63100.21 → 122.15 AUC₍₀₋₅₎ 5102.97 5355.76 95.28  87.33 → 103.96 *Leastsquares geometric means. Based on analysis of natural log-transformedpharmacokinetic parameters. ^(†)Lower confidence interval limits <80.00%and upper confidence interval limits >125.00% are shown in red.‡Metformin was co-administered with HCTZ and warfarin. AUC = area underthe curve; C_(max) = maximum plasma concentration; HCTZ =hydrochlorothiazideEthinyl Estradiol

FIG. 5 shows the mean±standard error plasma concentrations of ethinylestradiol after oral administration of single 0.06 mg Doses (2×0.03 mg)of ethinyl estradiol (with levonorgestrel) to healthy female volunteerswith a single 40 mg (2×20 mg) dose of oral octreotide acetate or withplacebo. As illustrated in FIG. 5, the arithmetic mean plasmaconcentrations of ethinyl estradiol were comparable after administrationwith oral octreotide compared to placebo. This was also observed for themajority of the individual subjects. The arithmetic (Table 11) andgeometric (Table 12) mean values for C_(max) and AUC₀₋₅ were comparable.The GMRs were 92.05% and 94.36%, respectively, and the 90% CIs werecontained within 80.00% to 125.00% (Table 12), indicating no effect oforal octreotide on the exposure to ethinyl estradiol.

TABLE 11 Summary of Pharmacokinetic Parameters for Ethinyl EstradiolAfter Oral Administration of Single 0.06 -mg Doses (2 x 0.03 mg) ofLevonorgestrel/Ethinyl Estradiol to Healthy Female Volunteers With andWithout a Single 40-mg (2 x 20 mg) Dose of Oral Octreotide Acetate OralOctreotide Parameter* With Without C_(max) (ng/mL) 103 ± 212 (14)  113 ±28.7 (14) T_(max) (h) 2.75 (14) 1.79 (14) [1.50-5.00] [1.00-2.00]AUC₍₀₋₅₎ (h × ng/mL) 351 ± 83.5 (14) 370 ± 80.2 (14) *Mean ± standarddeviation (N) except T_(max) for which the median (N) [Range] isreported. AUC = area under the curve; C_(max) = maximum plasmaconcentration; T_(max) = time of maximum plasma concentration

TABLE 12 Statistical Comparison of Pharmacokinetic Parameters forEthinyl Estradiol After Oral Administration of Single 0.06-mg Doses (2 ×0.03 mg) of Levonorgestrel/Ethinyl Estradiol to Healthy FemaleVolunteers With and Without a Single 40-mg (2 × 20 mg) Dose of OralOctreotide Acetate Geometric Mean* Geometric Mean Ratio (%)^(†)Parameter Test Reference Estimate 90% Confidence Interval EthinylEstradiol with oral octreotide vs Ethinyl Estradiol with Placebo C_(max)100.61 109.30 92.05 83.48 101.49 AUC₍₀₋₅₎ 341.52 361.96 94.35 86.19103.29 *Least squares geometric means. Based on analysis of naturallog-transformed pharmacokinetic parameters. ^(†)Lower confidenceinterval limits <80.00% and upper confidence interval limits >125.00%are shown in red. ‡Ethinyl estradiol was co-administered withlevonorgestrel. AUC = area under the curve; C_(max) = maximum plasmaconcentrationNorgestrel (Levonorgestrel)

As part of the analysis of ethinyl estradiol PK samples by the study'sbioanalysis lab, analysis of levonorgestrel concentration levels (asnorgestrel) were also performed.

FIG. 6 shows the mean±standard error plasma concentrations of norgestrelafter oral administration of single 0.30 mg Doses (2×0.150 mg) oflevonorgestrel (with ethinyl estradiol) to healthy female volunteerswith a single 40 mg (2×20 mg) dose of oral octreotide acetate or withplacebo.

As illustrated in FIG. 6, the arithmetic mean plasma concentrations ofnorgestrel over the initial 3 hours were lower after administration withoral octreotide compared to placebo (FIG. 6).

Although there was variability in the pattern among the individualsubjects, this lowering of plasma concentration of norgestrel wasobserved for the majority of subjects. The arithmetic (Table 13) andgeometric (Table 14) mean values for C_(max) and AUC₀₋₅ were lowerduring concomitant administration. The GMRs were 62.02% and 76.11%,respectively, and neither 90% CI was contained within 80.00% to 125.00%(Table 14). There was also a trend toward a longer median T_(max) whenlevonorgestrel was administered with oral octreotide, 2.00 vs 1.03 hwith a shift upward in the range (Table 13).

Overall, exposure to norgestrel is lower when administered with oraloctreotide.

TABLE 13 Summary of Pharmacokinetic Parameters for Norgestrel After OralAdministration of Single 0.30 mg Doses (2 × 0.150 mg) ofLevonorgestrel/Ethinyl Estradiol to Healthy Female Volunteers With andWithout a Single 40 mg (2 × 20 mg) Dose of Oral Octreotide Acetate OralOctreotide Parameter* With Without C_(max) (ng/mL)  4192 ± 1737 (14) 6584 ± 2108 (14) T_(max) (h) 2.00 (14) 1.03 (14) [1.00-5.00][0.75-4.00] AUC₍₀₋₅₎ (h × ng/mL) 13542 ± 5124 (14) 17528 ± 5543 (14)*Mean ± standard deviation (N) except T_(max) for which the median (N)[Range] is reported. AUC = area under the curve; C_(max) = maximumplasma concentration; T_(max) = time of maximum plasma concentration

TABLE 14 Statistical Comparison of Pharmacokinetic Parameters forNorgestrel After Oral Administration of Single 0.30-mg Doses (2 × 0.150mg) of Levonorgestrel/Ethinyl Estradiol to Healthy Female VolunteersWith and Without a Single 40-mg (2 × 20 mg) Dose of Oral OctreotideAcetate Geometric Mean* Geometric Mean Ratio (%)^(†) Parameter TestReference Estimate 90% Confidence Interval Norgestrel with oraloctreotide vs Norgestrel with Placebo C_(max) 3831.65 6177.76 62.0253.98 → 71.26 AUC₍₀₋₅₎ 12584.37 16535.56 76.10 67.04 → 86.40 *Leastsquares geometric means. Based on analysis of natural log-transformedpharmacokinetic parameters. ^(†)Lower confidence interval limits <80.00%and upper confidence interval limits >125.00% are shown in red.‡Levonorgestrel was co-administered with ethinyl estradiol. AUC = areaunder the curve; C_(max) = maximum plasma concentration

CONCLUSIONS

Based on C_(max) and AUC₀₋₅, there was no significant effect of oraloctreotide acetate on the exposure to R-warfarin, S-warfarin, metformin,or ethinyl estradiol. There was a trend toward a lower C_(max) andAUC₀₋₅ when HCTZ was administered with oral octreotide. There weredecreases in C_(max) and AUC₀₋₅ when levonorgestrel was administeredwith oral octreotide.

The invention claimed is:
 1. A method of administering oral octreotideto a female subject in need thereof wherein said subject is also in needof a contraceptive method, comprising (a) administering to the subjectoral octreotide; and (b) counseling the subject to avoid concomitant useof a combined oral contraceptive.
 2. The method of claim 1, wherein thecombined oral contraceptive comprises levonorgestrel.
 3. A method ofadministering oral octreotide to a female subject in need thereofwherein said subject is administered a combined oral contraceptive,comprising (a) administering to the subject oral octreotide; and (b)counseling the subject to use a back-up method of contraception or touse an alternative non-hormonal method of contraception.
 4. The methodof claim 3, wherein the combined oral contraceptive compriseslevonorgestrel.
 5. The method of claim 1, wherein the subject hasacromegaly.
 6. The method of claim 1, wherein the subject has severediarrhea or flushing episodes associated with metastatic carcinoidtumor.
 7. The method of claim 3, wherein the subject has acromegaly. 8.The method of claim 3, wherein the subject has severe diarrhea orflushing episodes associated with metastatic carcinoid tumor.
 9. Amethod of administering oral octreotide to a female subject in needthereof wherein said subject is also in need of a contraceptive method,comprising (a) administering to the subject oral octreotide; and (b)counseling the subject to avoid concomitant use of a contraceptive whichcomprises levonorgestrel or to use a back-up method of contraception orto use an alternative method of contraception.
 10. The method of claim9, wherein the contraceptive which comprises levonorgestrel is an oralcontraceptive.
 11. The method of claim 9, wherein the contraceptivewhich comprises levonorgestrel is not an oral contraceptive.
 12. Themethod of claim 11, wherein the contraceptive is an intrauterine device.